This proposal requests support for a Keystone Symposia meeting entitled Evolving Approaches to Early-Stage Drug Discovery, organized by Craig W. Lindsley and Linda Brady, which will be held in Snowbird, Utah from April 3 - 7, 2011. This meeting will cover multiple aspects of the challenges and opportunities facing drug discovery scientists, including the following: 1) diverse approaches to early stage discovery in a resource- constrained environment;2) evolution of preclinical drug discovery in academia;3) evolution of drug leads and target validation from the NIH Molecular Libraries Probe Centers Network (MLPCN);4) funding early stage or risky programs;5) external licensing of programs;and 6) advances in biomarkers and imaging to enable target selection and rapid go/no go decisions. The meeting goals are to bring together experts in all of these areas, present findings and share current understanding and hypotheses, and foster critical discussion of these topics. This will be the first meeting to bring together drug discovery scientists from the pharmaceutical industry, biotech, academia, and the NIH - each with unique missions and approaches - and to provide a forum for sharing their respective experiences. Furthermore, opportunities for interdisciplinary interactions will be significantly enhanced by the co-location of this meeting with the Keystone Symposia meeting on Drugs from Bugs: The Anti-Inflammatory Drugs of Tomorrow. PUBLIC HEALTH RELEVANCE: The pharmaceutical industry is facing massive attrition, mergers as well as failures in late clinical trials while, at the same time, academic drug discovery groups are emerging in greater numbers and with promising capabilities to deliver drug development candidates. The Keystone Symposia meeting on Evolving Approaches to Early-Stage Drug Discovery will serve to consolidate the field, advance the science of early stage drug discovery, and inform the biomedical community about resources to more rapidly develop therapeutics for difficult, high-risk targets by employing concepts and strategies to de-risk drug discovery efforts and maximize chances for success.